Nlrp3 Inflammasome Signaling Regulates the Homing and Engraftment of Hematopoietic Stem Cells (HSPCs) by Enhancing Incorporation of CXCR4 Receptor into Membrane Lipid Rafts

Abstract

Fast and efficient homing and engraftment of hematopoietic stem progenitor cells (HSPCs) is crucial for positive clinical outcomes from transplantation. We found that this process depends on activation of the Nlrp3 inflammasome, both in the HSPCs to be transplanted and in the cells in the recipient bone marrow (BM) microenvironment. For the first time we provide evidence that functional deficiency in the Nlrp3 inflammasome in transplanted cells or in the host microenvironment leads to defective homing and engraftment. At the molecular level, functional deficiency of the Nlrp3 inflammasome in HSPCs leads to their defective migration in response to the major BM homing chemoattractant stromal-derived factor 1 (SDF-1) and to other supportive chemoattractants, including sphingosine-1-phosphate (S1P) and extracellular adenosine triphosphate (eATP). We report that activation of the Nlrp3 inflammasome increases autocrine release of eATP, which promotes incorporation of the CXCR4 receptor into membrane lipid rafts at the leading surface of migrating cells. On the other hand, a lack of Nlrp3 inflammasome expression in BM conditioned for transplantation leads to a decrease in expression of SDF-1 and dangerassociated molecular pattern molecules (DAMPs), which are responsible for activation of the complement cascade (ComC), which in turn facilitates the homing and engraftment of HSPCs.

Inflammasomes and the Maintenance of Hematopoietic Homeostasis: New Perspectives and Opportunities

“…A series of studies by the Ratajczak group indicated a novel mechanism by which the NLRP3 inflammasome plays dual roles in the regulation of HSPC migration toward BM chemoattractants and also responds to myeloablative irradiation of the BM microenvironment to facilitate the homing and engraftment of transplanted cells [ 94 ]. The researchers first illustrated that the MBL-initiated ComC and coagulation cascade (CoaC) are involved in triggering the mobilization of HSPCs [ 95 ].…”

“…The researchers then proposed that the ATP-induced NLRP3 inflammasome acts as a neutralizer that connects purinergic signaling with the activation of the ComC, which is required for the egress of HSPCs from the BM into the PB [ 98 ]. In fact, proper NLRP3 inflammasome expression in HSPCs is also required for the migration of HSPCs in response to BM-expressed homing factors [ 94 ]. Activation of the NLRP3 inflammasome in HSPCs promotes the incorporation of CXCR4 into membrane lipid rafts, which enhances the release of eATP in an autocrine/paracrine manner to facilitate the migration of HSPCs in response to an SDF-1 gradient [ 94 ].…”

“…In fact, proper NLRP3 inflammasome expression in HSPCs is also required for the migration of HSPCs in response to BM-expressed homing factors [ 94 ]. Activation of the NLRP3 inflammasome in HSPCs promotes the incorporation of CXCR4 into membrane lipid rafts, which enhances the release of eATP in an autocrine/paracrine manner to facilitate the migration of HSPCs in response to an SDF-1 gradient [ 94 ]. NLRP3 inflammasome deficiencies within the BM of transplantation recipients induces a negative effect on the homing and engraftment of transplanted HSPCs, which may be due to the reduced mRNA expression of SDF-1 and certain DAMPs responsible for ComC activation [ 94 ].…”

“…Activation of the NLRP3 inflammasome in HSPCs promotes the incorporation of CXCR4 into membrane lipid rafts, which enhances the release of eATP in an autocrine/paracrine manner to facilitate the migration of HSPCs in response to an SDF-1 gradient [ 94 ]. NLRP3 inflammasome deficiencies within the BM of transplantation recipients induces a negative effect on the homing and engraftment of transplanted HSPCs, which may be due to the reduced mRNA expression of SDF-1 and certain DAMPs responsible for ComC activation [ 94 ]. Sustained activation of the NLRP3 inflammasome during mobilization induces the release of ROS and mitochondrial DNA from eATP-activated cells.…”

“…Moreover, inflammasomes are activated during sterile inflammation, which induces intracellular caspase-1 to promote the maturation of proinflammatory cytokines, the secretion of IL-1β and IL-18, and pyroptosis [ 94 , 98 ]. In addition to their proinflammatory properties, these two cytokines exert several other pleiotropic effects during hematopoiesis.…”